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Category: genetics

A poorly “cleaned” brain increases the risk of psychosis

A new study from the University of Geneva points to the brain’s waste-clearance system — the glymphatic system — as a possible piece of the psychosis puzzle. In people with 22q11.2 deletion syndrome, a high-risk genetic condition, researchers found developmental differences in an MRI-derived marker linked to glymphatic function, along with associations to hippocampal excitation/inhibition balance and psychosis vulnerability.

A team from UNIGE shows that early alterations in the brain’s clearance system could contribute to vulnerability to psychosis.

How can we explain the onset of psychotic symptoms characteristic of schizophrenia? Despite their major and often irreversible impact on intellectual abilities and autonomy, the biological mechanisms that precede their emergence remain poorly understood. A team from the Department of Psychiatry at the Faculty of Medicine and the Synapsy Center for Neuroscience Research in Mental Health at the University of Geneva (UNIGE) provides new insight into this question. Early dysfunction of the glymphatic system, the network responsible for removing waste from the brain, could be a key vulnerability factor. This research has been published in Biological Psychiatry: Global Open Science.

Hallucinations and delusions are among the characteristic psychotic symptoms of schizophrenia spectrum disorders, which may also be accompanied by social withdrawal and cognitive decline. These disorders, considered neurodevelopmental conditions, most often emerge during adolescence or early adulthood and have an estimated prevalence of 0.5–3% in the general population.

Understanding protein motion could greatly aid new drug design

For many people, “protein” is the key element of a food order. However, beyond the preferred choice of meats or plant-based alternatives, proteins encompass a large class of complex biomolecules whose chemical structure is encoded in our genes. Proteins have critical functions in living cells; they help repair and build body tissues, drive metabolic reactions, maintain pH and fluid balance, and keep our immune systems strong.

To perform their important functions, many proteins have a dynamic molecular structure capable of adopting multiple conformations. For a long time, scientists have suspected that proteins don’t change shape at random. Instead, they seem to move according to deep, slow rhythms—like a building that sways gently in the wind rather than shaking violently.

Those slow rhythms guide how a protein bends, twists, and shifts between its different forms. If one could understand those rhythms, one might be able to predict—and even hurry along—the protein’s movements.

Energy crisis drives T cells to exhaustion in tumors

The immune system’s killer T cells do a commendable job of detecting and destroying cancer cells. But the harsh environment at the heart of tumors often saps them of their vitality, pushing them into a state of permanent lassitude called “terminal exhaustion.” The phenomenon accounts for why so many tumors resist routine immune clearance and even cancer immunotherapies devised to stimulate their lethal capabilities.

Terminal exhaustion is characterized by an accumulation of dysfunctional mitochondria—the bean-shaped energy generators in cells—and extensive genetic reprogramming that stalls proliferation and hobbles the cell-killing weaponry of T cells. Yet how mitochondrial dysfunction is linked to genetic reprogramming in the cells was unclear. No longer. Researchers in the journal Nature show that how the accumulation of useless mitochondria is linked to T cell exhaustion through a complex series of subcellular processes.

The researchers report in their paper that the glut of dysfunctional mitochondria enhances the activity of a cellular protein digesting machine, known as the proteasome, in T cells. The activated proteasome, they show, preferentially degrades mitochondrial heme-containing proteins.

As might be expected, this bias leads to quite the buildup of heme in the cells, resulting in the generation of a functionally distinct form of the molecule referred to as “regulatory heme,” which zips into the nucleus through a transporter named PGRMC2. There it binds to a transcription factor, a protein that regulates gene expression, causing its degradation. This kicks off a series of events that culminates in the activation of genetic programs known to induce terminal exhaustion.

The researchers show that genetic disruption of PGRMC2 abrogates this effect, keeping anti-tumor T cells in a functionally vibrant state, suggesting it is a potential drug target for the enhancement of T cell-activating cancer immunotherapies.

The researchers also examined how the pharmacological inhibition of the proteasome with an existing leukemia therapy, bortezomib, might affect CAR-T cells. Like bortezomib, CAR-T therapy is currently used to treat B cell acute lymphoblastic leukemia (B-ALL).

“We found that the transient and low-dose addition of bortezomib to CAR-T cell cultures during manufacturing reduces exhaustion-associated programs in the cells and induces durable reprogramming of their gene expression patterns to maintain them in a proliferative and functionally vibrant state,” said the author. ScienceMission sciencenewshighlights.

Continue reading “Energy crisis drives T cells to exhaustion in tumors” | >

Mitochondria Delivery Method Rescues Parkinson’s in Mice

Scientists used red blood cells as membrane donors to encapsulate healthy mitochondria and send them into diseased cells, achieving improvements across multiple models and conditions [1].

The delivery problem

Mitochondrial diseases are a diverse group of disorders that arise when mitochondria malfunction. They are often caused by mutations in mitochondrial DNA (mtDNA) itself or in nuclear genes encoding mitochondria-related proteins.

Unraveling the secrets of telomerase, an enzyme linked to aging and cancer

A central question in molecular biology is how cells protect their chromosomes from damage during repeated cell division. At the heart of this protective process is an enzyme called telomerase. Now an international research team has mapped the three-dimensional structure of telomerase in the yeast Saccharomyces cerevisiae, a widely used model organism in genetics.

Using cutting-edge technology, the scientists were able to visualize the architecture of this complex enzyme in unprecedented detail, uncovering unexpected features that may explain how it functions.

This major discovery was the result of an international collaboration between Pascal Chartrand, a professor in the Department of Biochemistry and Molecular Medicine at Université de Montréal, and researchers from Université de Sherbrooke and the MRC Laboratory of Molecular Biology in the U.K. Their findings were recently published in Science.

What changes happen in the aging brain?

A new study from the Salk Institute maps how the aging brain changes at the epigenetic level — cell type by cell type.

The researchers created one of the most detailed single-cell atlases yet of the aging mouse brain, spanning 8 brain regions, 36 cell types, and hundreds of thousands of cells. They found major age-related changes in DNA methylation, chromatin structure, and gene activity, with some of the strongest changes appearing in non-neuronal cells.

This kind of work matters because it moves brain aging closer to mechanism — not just describing decline, but identifying the molecular regulatory shifts that may drive vulnerability to neurodegenerative disease.

Highlights Salk researchers create epigenetic atlas of cell type-specific changes in the aging mouse brain The atlas represents eight different brain regions and 36 different cell types, and shows clear epigenetic differences associated with different ages The new resource—available publicly on Amazon Web services—can be used to unravel age-related contributions to neurodegenerative diseases like Alzheimer’s, Parkinson’s, and ALS LA JOLLA—Neurodegenerative diseases affect more than 57 million people globally. The incidence of these diseases, from Alzheimer’s to Parkinson’s to ALS and beyond, is expected to double every 20 years. Though scientists know aging is a major risk factor for neurodegenerative diseases, the full mechanisms behind aging’s impact remain unclear.

DNA shape explains crucial gene-therapy challenges

CRISPR is a powerful DNA-editing tool that has underpinned huge advancements in human health care in the last decade. It is a precision tool, but is not perfect, and misplaced DNA edits can compromise safety and efficacy, costing billions each year. Researchers at the MRC Laboratory of Medical Sciences (LMS), Imperial College London and the University of Sheffield have published research in Nature showing that the physical twisting of DNA plays an important role in these mistakes. Using a newly developed platform of tiny (nanometer-sized) DNA circles, called DNA minicircles, the team captured never-before-seen interactions between CRISPR and DNA, providing insights that could help eradicate errors altogether.

CRISPR-Cas9 has transformed biology by giving scientists a programmable way to cut and edit DNA. Its ever-growing impact includes groundbreaking therapies for genetic diseases such as sickle cell anemia and an increasing role in personalized cancer treatment and rapid diagnostics. But even carefully designed CRISPR systems can sometimes cut DNA sequences that were not the intended targets.

“It’s a tool that is not perfect and can introduce errors and make edits where it shouldn’t make them,” says Professor David Rueda, head of the Single Molecule Imaging group at the LMS and Chair in Molecular and Cellular Biophysics at Imperial College London. “And it’s an important problem for the industry. It’s been estimated to be $0.3 to $0.9 billions per year in industry costs, in profiling off-targets, redesigning guides and delays.”

Characterization of a Splice Variant in FLNA Associated With Periventricular Nodular Heterotopia

This study broadens the phenotypic and genetic spectrum of PNH, demonstrating a dual PNH phenotype associated with a bi‑transcript mechanism and mosaic inheritance, including tissue‑specific mosaicism.

PNH is a neurodevelopmental brain malformation characterized by failure of the gray matter to properly migrate to the cerebral cortex during embryonic development. This results in ectopic localization around the ventricular ependyma.1 MRI serves as the primary diagnostic tool, showing bilateral periventricular gray matter nodules with a signal intensity similar to that of normal cortical gray matter.2,3 Its primary clinical manifestation is epilepsy, which is often accompanied by intellectual disabilities and learning difficulties.2,3 PNH is genetically heterogeneous and is linked to variants in multiple genes, including ARFGEF2, ERMARD, NEDD4L, ARF1, and MAP1B, as well as abnormalities in chromosome 5. Among these, pathogenic variants in FLNA are the most common genetic causes.4

FLNA is located at Xq28 and comprises 47 exons,5 encoding a 280 kDa actin binding protein, called filamin A. The N-terminal region contains an actin binding domain (ABD) and a rod-like structure composed of 24 immunoglobulin-like repeats. ABD interacts with actin to stabilize the cytoskeletal architecture and plays crucial roles in maintaining cell shape, migration, and transmitting mechanical force. FLNA regulates cellular migration and extension processes via interactions with several signaling proteins, including small GTPases Rac/Rho, TRAF2, integrins, and BRCA2.6–8 This gene possesses at least 2 transcription initiation sites (ENST00000369850.8 and ENST00000610817.4) that use distinct promoters and demonstrate tissue-specific expression.6–8 Rat FLNA-knockdown models exhibit impaired neuronal migration and elevated epileptic susceptibility.

Hearing research traces evolution of key inner ear protein

In the intricate machinery of the inner ear, hearing begins with a protein that moves a few billionths of a meter up to 100,000 times per second. That protein, called TMC1, sits at the tips of sensory hair cells deep in the snail-shaped cochlea. When sound waves move these microscopic hairs, TMC1 acts as a channel, opening and allowing charged particles to flow into the cell and trigger an electrical signal to the brain.

Without TMC1, that signal never starts. Mutations in the TMC1 gene are a well-known cause of hereditary hearing loss in humans. Because of this central role, TMC1 is an attractive target for researchers designing gene therapies aimed at restoring hearing. Several groups are testing ways to supply working copies of the gene or fix harmful mutations.

For these efforts to be safe and effective, scientists need to know in detail how TMC1 is built, how it opens, and which parts of the protein are most sensitive to change. However, the hair-cell system that includes TMC1 is so complex, sensitive, and hard to access that it is notoriously difficult to take apart and study directly.

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